There has been good progress made in the area of gene therapy for hemophilia during the past 5 years. The goal is to continue our studies towards hepatic gene transfer into the liver with the goal of developing a curative therapy for hemophilias A and B. Our laboratory is interested in comparing three promising viral vectors for hepatic gene transfer for hemophilia. We plan to do studies to further understand the biology of the vectors as it relates to transduction of hepatocytes in vivo. This information will be used to develop preclinical trials for these vectors by testing the most promising approaches in two animal models, mouse and canine hemophilias. The aims are to: (1) Compare the safety and hepatic transduction efficiencies of mouse Moloney, human foamy, and human lenti viruses, and determine their abilities to express clotting factors in vivo. (2) Further develop rAAV vectors for hepatic gene therapy for hemophilia. (3) Determine the potential use of an Adenoviral/AAV hybrid virus that is devoid of all viral genes for hemophilia gene therapy. We believe these studies will further our understanding of three important classes of viral vectors for hepatic gene transfer and develop the principles required for a clinical trial for the treatment of hemophilias A and B.